Significant research has been performed over the past 60 years to develop formulations containing ascorbic acid (Vitamin C) that are stable to atmospheric oxidation. That research has been reported in numerous publications and patents, especially for formulations containing low concentrations of this important antioxidant. For example, Ciminera and Wilcox, "Stable Ascorbic Acid Solution for Parenteral Use" in J. Am. Pharm. Assoc. Sci. Ed. 35:363 (1946) discloses buffering aqueous ascorbic acid solutions with an alkaline sodium salt. Takashima, et al., "Ascorbic Acid Esters and Skin Pigmentation" in Am. Perfumery and Cosmetics 86:29 (July 1971) discloses the use of ascorbic acid esterified at the hydroxyl group of the third carbon with a phosphate group to yield a molecule that is stable in alkaline pH solutions.
U.S. Pat. No. 2,400,171 (Ruskin) discloses the conversion of ascorbic acid to its calcium or zinc salt to maintain stable aqueous solutions in the pH range of 7 to 7.3. U.S. Pat. No. 2,442,461 (Karrer) discloses stabilizing aqueous solutions of calcium ascorbate by adding an aliphatic thiocarboxylic acid, and maintaining the pH of the solution in the range of 5.2 to 5.6. U.S. Pat. No. 2,585,580 (Opplt) discloses the stabilization of ascorbic acid with thio-sugars, and maintaining the pH of the resulting solution in the range of 4.0 to 6.5. U.S. Pat. No. 4,367,157 (Sherman) discloses stabilizing aqueous ascorbic acid solutions in the pH range of 4 to 7 by adding monothioglycerol.
U.S. Pat. No. 4,372,874 (Modrovich) discloses adding a desiccant to a solution of ascorbic acid to entrap water and provide a residual water content below 0.5 weight percent, thereby forming a stable form of ascorbic acid. U.S. Pat. No. 5,140,043 (Darr et al.) discloses the stabilization of at least 1% (w/v) ascorbic acid by combining this material with equal parts water and a carrier comprising an alkylene glycol, and optionally a hydroxyalkylcellulose at a pH no greater than 3.5.
U.S. Pat. No. 5,296,249 (Todd) disclosed micron sized particles of ascorbic acid in a suspension medium in which the particles were insoluble. U.S. Pat. No. 5,308,621 (Taylor et al.) showed fine, particulate ascorbic acid suspended in a pharmaceutical carrier (such as a glycol or petroleum jelly) for transdermal systemic administration. U.S. Pat. No. 5,587,149 describes a polyethylene glycol-in-oil emulsion of ascorbic acid.
Ascorbic acid is biologically significant for many reasons, and has been found to have several different activities in the skin, as pointed out by Englard and Seifter, "The Biochemical Functions of Ascorbic Acid" in Ann. Rev. Nutri. 6:365 (1986). This vitamin has been found to be an antioxidant in blocking the lipid peroxidation of the skin, as demonstrated by Kunert and Tappel, "The Effect of Vitamin C on In-Vivo Lipid Peroxidation in Guinea Pigs as Measured by Pentane and Ethane Production" in Lipids 18:271 (1983). Furthermore, a significant amount of research has been published that describes the effects ascorbic acid has upon scavenging oxygen free radicals under a variety of normal and pathological conditions. Some of this research is included in the following partial list of texts on the subject.
1. Oxidative Stress, H. Sies, ed. (Academic Press, 1985)
2. Free Radicals, Aging and Degenerative Diseases, J. Johnson, Jr., R. Walford, D. Harmon and J. Miguel, eds. (Alan Liss, Inc., New York, 1986) 3. Biological Role of Reactive Oxygen Species in Skin, O. Hayaishi, S. Inamura and Y. Mayachi, eds. (Elsevier Press, New York, 1987) 4. Free Radicals in Biology and Medicine, B. Halliwell and J. Gutteridge, eds. (Clarendon Press, Oxford, 1985).
Additionally, ascorbic acid has been shown to stimulate collagen synthesis in-vitro, as detailed in the article entitled "Regulation of Collagen Biosynthesis by Ascorbic Acid: A Review" by S. Pinnell in Yale J. Biol. Med. 58:554 (1985).
As indicated by these references, although ascorbic acid is important to the skin, it is difficult to stabilize in topical preparations (such as dermatological, ophthamological or cosmetic formulations), particularly at the higher concentrations needed for maximum activity. The difficulties in preparing a stable topical preparation stem from the fact that ascorbic acid is an .alpha.-ketolactone having a double bond between the second and third carbon atoms of the structure, and hydroxyl groups at the second and third carbon atoms, and is therefore a moderately strong reducing agent. The pK of the molecule is 4.2, which means that one of the hydroxyl groups is 50% ionized at this pH value. At higher pH values the ascorbate anion becomes notoriously unstable. This instability is a result of several factors including stereochemical strain due to polar repulsion, the tendency of the molecule to disproportionate to dehydroascorbic acid (or dehydroascorbate anion) and ascorbic acid (or ascorbate anion) in the presence of a one-electron oxidant, or by a simple hydration reaction due to the attack of either a hydronium ion (or hydrogen ion) or a hydroxyl ion on the molecule, which opens the lactone ring structure.
There have been pharmaceutical (such as dermatological and ophthamological) and cosmetic products previously developed and marketed which contain esters of ascorbic acid in non-aqueous vehicles. However, none of these formulations contained high levels of the ascorbic acid ester that simultaneously demonstrated efficacy and stability. These non-aqueous formulations primarily used esters, fatty acids and fatty alcohols as the vehicles for delivery of the ascorbic acid ester.